This is a revised competing continuation application for NIAID grant R01 AI48526, Novel TB Preventive Regimens for HIV Infected Adults. The purpose of this trial is to determine the efficacy of three novel treatments on the risk of TB in a population of HIV-infected adults in Soweto, South Africa. Over the past 4 years, we have built a productive research team in Soweto and have recruited 1150 HIV/latent TB co- infected adults into this trial. We have randomized these patients with HIV infection and a reactive tuberculin skin test to receive weekly rifapentine and INH (RPT/INH) for 12 weeks, twice-weekly rifampin and INH (RIF/INH) for 12 weeks, continuous INH daily indefinitely (INH-C), or the internationally accepted standard of INH daily for six months (INH-6) for the prevention of TB. RPT is a rifamycin-S derivative with antimicrobial activity similar to rifampin, but with a longer half-life. RPT is efficacious in the treatment of non-HIV-related TB, and has been shown in animal models to be a highly promising agent for treating latent TB. We hypothesize that the increased tuberculocidal activity and programmatic advantages of supervised, once- or twice- weekly regimens with rifamycin-based combinations will be more effective than INH-6. We also hypothesize that a continuous course of INH will be more effective than INH-6 because elimination of latent TB will be more thorough and prophylaxis will provide ongoing protection against incident TB infection. The current mean follow up for patients in the study is 1.4 years, and there have been 24 incidence cases of TB, for a rate of 1.5 cases per 100 person-years. We now propose to extend follow up for another 3 years, so that all participants will be followed at least 3 years, with a mean of 4.4 years. With a type I error of 0.05, we have power of 85-99% to detect superiority of the 3 experimental regimens vs. the control regimen, INH-6. This trial of TB preventive therapy in a setting of comprehensive HIV care for adults in a developing country setting will generate critically important data on alternative therapeutic options for TB control amongHIV- infected people that will be applicable throughout the world.